Impaired wound healing is a major problem for many surgical and burn patients but the causes of the healing abnormalities are not known. The hypothesis that topical growth factors can at least partially reverse the abnormalities of impaired healing has been proven. Previous works have focused on stimulating healing in two models of impaired healing, genetically diabetic C57BL/KsJ-db/db mice and in a similar malnutrition model. The obese, diabetic animals have insulin-resistant diabetes and significantly impaired healing. Unlike other rodent models, the majority of their healing results from granulation tissue formation and re- epithelialization, not contraction. Individual application of several growth factors (PDGF, bFGF, IGF-1, IGF-II or TGF-a) significantly augment healing in these animals. Growth factors were also found to reverse the healing deficit in malnourished animals. Since multiple growth factors with differing functions are active during healing, growth factor combinations should enhance healing to a greater extent than one. Preliminary work has proven that growth factor combinations do have synergistic effects on tissue repair. The first aim will be to continue to examine the role of growth factors combinations in reversing healing abnormalities in clinically relevant impaired healing models. The specific growth factors to be examined will be the "competence" factor PDGF, the "progression" factor IGF-II and the keratinocyte mitogen TGF-alpha. The focus of the second aim will be to delineate at least some of the causes of healing impairments. The hypothesis directing the second aim is that healing abnormalities are related to impaired interactions with growth factors. In the sound, growth factor synthesis may be decreased, growth factor degradation may be increased or the cellular response to growth factors may be an impaired. Comparisons of healing between wounds that heal normally and those are impaired will be performed. Histology and immunohistochemistry will be used to compare cellular entry and differences in collagen deposition. Studies will continue with identifying the amounts of PDGF, IGF-II, TGF-alpha and TGF-beta. Interactions with growth factor receptors will be designed to identify which receptors are responsible for specific growth factor activities. Initial studies will try to identify which of the IGF receptors is responsible for IGF activity in wound healing. The aim will be to learn how impaired healing responds to growth factors. The same techniques as for the second aim will be used except that changes in cellularity, collagen deposition, growth factor and receptor interactions will be examined after growth factor application. The ultimate goal is to use this knowledge to treat clinical healing problems.